During the process of carcinogenesis, tumor cells within a solid tumor undergo many phenotypic alterations which influence their pattern of growth and spread. Our working model in the proposed program is that a key element in the progression of prostate cancer involves the exposure of the tumor cells to laminin; laminin, as a signalling molecule in the basement membrane, interacts with the alpha6 beta1 integrin. The alpha6 beta1 heterodimer is activated by clustering, signalling the cells to produce and secrete proteases which degrade the basement membrane. Although cellular adhesion is important for tumor formation, the post-adhesion signalling results in the production of proteases for increasing the invasive potential of the tumor cells. The major hypothesis to be tested is that cellular adhesion and signalling by laminin through clustering of the integrin alpha6 is important for triggering the invasion cascade by increasing the. production of proteases. Continued signalling of the integrin in the absence of basement membrane is achieved by the tumor cells through their secretion of laminin. We will test whether alpha6 integrin units confer an invasive phenotype using the criterion of invasive tumor formation in scid mice and the in vitro end points of protease activity and cellular migration on basement membrane substrates. The cellular content of alpha6 will be altered both by selection of over and under-expressors of alpha6 by a FACS technique and by transfection of the alpha6 gene. We will also determine if the clustering of the alpha6 integrin mediates a signal to produce, secrete or activate the metalloproteinases. We also will determine whether the clustering of the integrin receptor increases the ability of the cells to migrate on laminin and collagen IV. Finally, we will determine whether the tumor cells which are high and low secretors of the alpha6 ligand, laminin, (which normally clusters the integrin), are altered in their ability to migrate, secrete proteases or form tumors which invade the tissues of scid mice. These observations of integrin alterations affecting tumor cell progression will contribute to our knowledge about the basic biology of integrin clustering and the signal for protease production and cellular migration. In addition, these observations potentially will provide prognostic indicator(s) to the staging of prostatic carcinoma.
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